Diabetes Mellitus type 2 affects over 200 million individuals worldwide. While DM2 has a strong familial component, the search for individual causative genes has been only mildly fruitful and development of DM2 is thought to depend on the combination of a number of genetic and environmental factors. With the cost for whole- genome sequencing of individuals in reach as well as the maturation of technologies for quantifiably measuring tens of thousands of biomolecules, there exists a tremendous opportunity to understand the genetic and bimolecular factors which underlie the progression to DM2. Our lab has recently developed a novel pipeline termed integrative personal omics profiling (iPOP) which combines genomic, transcriptomic, proteomic and metabolomics profiles with computational tools to comprehensively investigate the molecules and pathways that change during disease onset and progression. We propose to perform whole-genome sequencing and longitudinal iPOP analysis on a cohort of overweight individuals either high-risk or low-risk for progression to DM2. For this cohort, we will analyze blood samples at the onset of the study, after a moderate weight gain and after a period of significant weight loss. We hypothesize that through iPOP analysis we can elucidate novel molecular factors and pathways which change in response to weight gain and loss and which differ between high- and low-risk individuals. Through this analysis we will offer an unprecedented view of the changing molecular landscape underlying acquired insulin resistance.